Candidate: Dr. Carlsson's long-term goal is to become an independent clinical investigator in Alzheimer's disease (AD) and its relationship to vascular risk factors. As part of this K23 award, Dr. Carlsson will develop a career in patient-oriented research by obtaining advanced training in clinical research design, biostatistics, cognitive theory and testing, epidemiology, and data management through the UW Masters of Science in Population Health Sciences Program, the UW Graduate School Department of Psychology, and the Capstone Certificate Program in Fundamentals of Clinical Research. Furthermore, she will complete her training through the Clinical Investigator Preparatory Pathway (CIPP, NIH K30). She will also obtain advanced training in ethical and regulatory issues that govern human subjects research. Environment: The University of Wisconsin Medical School is a premier research institution that has recently identified Geriatrics and Neurosciences as two of the top five priority areas for research. In addition to the UW Memory Research Program and Section of Geriatrics and Gerontology, Dr. Carlsson will have access to the following resources for the proposed K23 award: the Wisconsin Alzheimer's Institute; the Wisconsin Registry for Alzheimer's Prevention; the Institute on Aging; the VA Geriatric Research, Education and Clinical Center (GRECC); and the General Clinical Research Center (GCRC). Research: Given the evidence from epidemiological, animal, and clinical research suggesting that statins may have a preventive role in AD, Dr. Carlsson proposes to evaluate the effect of simvastatin on cerebrospinal fluid (CSF) and plasma markers of AD progression, central nervous system (CNS) cholesterol metabolism, and CNS inflammation in a population of middle-aged adults at increased risk for developing AD. 100 men and women without dementia from the Wisconsin Registry for Alzheimer's Prevention will be recruited for participation in a 9-month randomized, controlled trial evaluating the effects of simvastatin 80 mg nightly vs. placebo on 1) CSF amyloid beta-42 (Abeta42) levels; 2) plasma markers of CNS cholesterol metabolism; and 3) CSF and plasma markers of inflammation. Participants will have fasting labs drawn, CSF collected, and cognitive testing done at baseline and 9-month follow-up. Additional visits at 1, 3, and 6 months will assess side effects. Cognitive testing will also be repeated at the 3-month follow-up. Outcome measures at 9 months will be compared to baseline. Results will be analyzed by apolipoprotein E4 status.